This project will examine the hypothesis that NMDA receptor hypofunction within hippocampal regions model central features of the cognitive symptoms of schizophrenia. Neuropsychological studies in schizophrenic patients have identified a core deficit in episodic memory and studies on animals strongly suggest an essential role for NMDA receptors in the hippocampus is the storage and recall of associations that underlie our capacity for episodic memory. The proposed studies will combine our own recent development of a novel protocol for the assessment of specific features of episodic memory in animals and a novel technique for spatially and temporally selective NMDA receptor knockout developed in Robert Greene's laboratory. In collaborative studies we will explore the role of NMDA receptors in specific components of the hippocampal circuit. We expect to dissociate a critical role for NMDA receptors in area CA3 in the association of stimuli and their context from a critical role for NMDA receptors in area CA1 in memory for sequential events. We also expect to dissociate a critical role for CA3 and CA1 NMDA receptors in "all-or-none" episodic memory retrieval from a crucial role for NMDA receptors in the perirhinal and entorhinal cortex in recognition based on a sense of familiarity. Finally, we expect to identify a selective role for CA3 NMDA receptors in the linking of related memories supporting inferences from memory. These findings will provide insights about the functional circuitry of hippocampal NMDA receptors, of strong relevance to other center projects that employ functional imaging, molecular and cellular biology, and computational modeling.